11alpha-acyloxy-17alpha-halo-4-pregnene-3, 20-dione and process



11a-ACYLOXY-17ot-HALO-4-PREGNENE 3Q0 DIONE AND PROCESS Douglas A. Lyttle and Robert H. Levin, Kalamazoo Township, Kalamazoo County, 1 Mich., assignors to The Upjohn Company, Kalamazoo, Mich., (a corporation of Michigan No Drawing. Application August 27, 1953', Serial N0. 376,988

14 Claims. tot. 260-39145 The present invention relates to novel steroid esters and is particularly concerned with llu-acyloxy-flmhalo' 4-pregnene-3,20-diones and with a process for the production thereof. i

The novel compounds of the present invention are represented by the following formula:

"ice

2 16dehydroprogesterone yields 11e-acyloxy-16,l7-oxidoprogesterone. The epoxide is then opened with hydrogen bromide, and the resulting l6-bromo-l7ot-hydroxy derivative treated with zinc dust to remove the l6-bromine. The lla-acyloxy-l7cxhydroxyprogesterone, thus-obtained, on saponification and oxidation yields the known 17ozhydroxy1l-ketoprogesterone (ZI-Desoxy E) which on treatment with lead tetraacetate, followed by saponification gives cortisone (1771,21-dihydroxy-4-pregnene-3,11,- ZO-trione), and on treatment with lithium aluminum hydride, withprotection of the 3- and ZO-lteto groups, gives 1 lot, l.7u-dihyroXyl-pregnene-Ii,ZO-dione (21Desoxy F), a new compound possessing pronounced inhibiting effect on the secretion of the adrenocorticotropic hormone (ACTH) and having value, therefore, in the treatment of diseases where oversecretion of ACTH and wherein Ac is the acyl radical of a carboXylic acid containing up to and including eight carbon atoms and X is a halogen atom selected from the class consisting of chlorine and bromine.

1 The novel compounds ofthis invention are prepared by selective dehydrohalogenation of 4,17adih&10-11otacyloXy-4pregnene-3,ZO-dione, i. e., by forming a 3-hydra- Zone of an 1lot-acyloxy-l7a-halo-4-pregnene8,ZO-dione by treating 1le-acyloxyt,17ct-dihalopregnane-3,ZO-diorie in the presence of an acid with an organic hydrazine capable of forming a hydrazone and hydrolyzing the 3- hydrazone group without simultaneously removing the 17Ct-ha1O atom. Forthis purpose any organic hydrazine containing two hydrogenatoms on one of the hydrazine nitrogen atoms canbe used. The hydrolysis of the 3- hydrazone group is advantageously effected by an exchange reaction with a ketaldoner The word ketaldone refers generically to aldehydes and ketones. For this purpose a ketaldone in which the 0x0 group is attached to an electrophylic group, as in pyruvic acid, pyru'vic aldehyde, and benzaldehydes, such-as meta-, para-, and ortho-hydroxy-benzaldehydes, and meta-, para-, andorthocarboxybenzaldehydes, is advantageous.

' It is an object of the present invention to provide novel 11d acyloxy-17a halo-4-pregnene-3,20-diones. Another object of the invention is to provide a process for the production of lla-acyloxy 17a halo-4-pregnene-3,20- dione. It is another object of thepresent invention to provide a method of a selective. dehydrohalogenatiojn, restricted' to the 4,5-position of the steroi-dmolecule; Other objectsof this invention .willbe apparent to'one skilled in the art to which this invention pertains.

The novel compounds, 1la acyloxy-17a-ha1o-4-pregnene-3,20-diones, of the present invention are stable, easily crystallizable solids which 'have not only pharmacological and physiological activity per set but are :also important intermediates in the production of active 11- oxygenated keto steroids. For example, dehydrohalogenation of an 11a-acyloxy-17-bromo-4-progesterone with pyridine and epoxidation of the thus-obtained l1a-acyloxy-.

adrenal hormones occurs, for example, in adrenal hyperplasia and pituitary basophilisrn (Cushings disease).

The starting compounds of the present invention are the 4,l7adihalo-llct-acyloXypregnane-3,ZO-diones. The acyl group can have substituents, such as halo, mercapto, methoxy, ethoxy, hydroxy, carboxy, carbalkoxy, and the like. They are prepared by treatment of lltx-hydroxypregnane 3,20 -dione or an 11a-acyloxypregnane-3,20- dione with an acid anhydride to form the corresponding enol ester a 3,1106,20 triacyloxy 4,l7(20)-pregnadiene, which by treatment with a hypohalous acid furnishes a 4,17ot-dihalo-11ot-acyloxypregnane-3,ZO-dione, as shown in Preparations 1 through 6.

In carrying out the process, 4,17-dihalo steroid of the selective dehydrohalogenation of a selected 4,17u-dihalo- 1la-acyloXypregnane-3,ZO-dione is dissolved in an organic solvent, such as doxane, acetic acid, acetone, dimethylformamide, tertiary butyl alcohol, ethanol, or mixtures of thesesolvents, with dioxane and acetic acid preferred, containing from about five to 25 percent water. To this solution is added, usually with continuous stirring, a solution of an organic hydrazine, such as semicarbazide, phenylhydrazine, 2,4-dinitrophenylhydrazine, para-nitrophenylhydrazine, ocor B-naphthylsemicarbazide, 2,4 and 3,5-dinitrophenylsemicarbazide, and other substituted hydrazines, with semicarbazide preferred. The reaction advantageously is carried out at a temperature between about fifteen and about forty degrees centigrade. er and lower temperatures, between about zero degrees and about degrees centigrade, however, are opera tive. The time'of reaction varies from about half an hour to twelve hours, or even longer, and during this period a color change from colorless to yellow or orange andrback to colorless or pale yellow is noted.

The llot acyloxy-l7ct-halo-4-pregner1e-3,ZG-tlione 3-substituted hydrazone thus-obtained can be isolated from the mixture by adding more water and filtering the precipitated compound but advantageously is immediately reacted in solution with an aldehyde or ketone without isolation. The aldehydes or ketones used are usually pyruvic acid, pyruvic aldehyde, benzaldehydes, such as hydroxybenzaldehyde and the carboxybenzaldehydes, and

halo-4-pregnene-3,ZO-dione, isisolated from the solutionby pouring the cooled solution into water, extracting with High The reaction a suitable solvent, such as dichloromethane, chloroform, ether or benzene, and evaporating the solvent from the resulting extract.

The following examples illustrate the process and products of the present invention but are not to be construed as limiting.

PREPARATION 1.3,1 1a,2()-TRIACETOXY-3,17 (20)- PREGNADIENE A mixture of.300 milligrams of lla-hydroxypregnane- 3,20-dione, fifteen milliliters of acetic anhydride, and 140 milligrams of para-toluenesulfonic acid monohydrate was heated to boiling and allowed to distil slowly for four hours, most of the excess acetic anhydride being distilled at the end of this time interval. cess acetic anhydride were removed under vacuum, and the resulting residue was cooled and dissolved in ether. The ether solution was washed with cold ten percent aqueous sodium bicarbonate solution and dried over anhydrous sodium sulfate. moved by filtration, and the ether was distilled. The residue was dissolved in warm alcohol and allowed to crystallize. The crystalline 3,1100,20-triacetoxy-3,17(20)- pregnadiene (150 milligrams) melted at 162-167 degrees centigrade. red analysis.

PREPARATION 2.--3,1 1a,20-TRIPROPIONOXY3 1 7 2O PREGNADIENE Using the procedure of Preparation 1, lla-hydroxypregnane-3,20-dione is converted to :3,11a-20-tripropioncity-3,17(20)-pregnadiene using propionic anhydride and para-toluenesulfonic acid.

PREPARATION 3 .3 ,1 :,20-TRIHEPTANOYLOXY-3 ,17()- PREGNADIENE l100 hydroxypregnane-3, 20-di0ne is converted by the procedure of Preparation 1 to 3,1100,20-triheptanoyloxy- 3,17(20-pregnadiene by heating for five hours with heptanoic anhydride and para-toluenesulfonic acid with toluene added as a solvent.

By the procedure of Preparations 1 through 3, other 3,1 10t,20wtriacyloxy 3,17(20)-pregnadienes are prepared by heating 11a-hy-droxypregnane-3,2'0-dione with a selected acid anhydride including: 3,1 1a,20-tr-ibutyroxy- 3,17(20) pregnadiene, 3,1100,20 trivaleroxy 3,17(20} pregnadiene, 3,110,20 triisovaleroxy-3,17(20) pregnadiene, 3 ,1 l00,20-trihexanoyloxy3, 17 20) apregnad-iene, 3,1 1a,20-trioctanoyloxy-3, 17 (20)-pregnadiene, 3,1111,20- tribenzyloxy-3,17'(20)-pregnadiene, and the like.

PREPARATION 4.-3 ,20-DIAcEToxY-1 lu-BENZOYLOXY- 3 1 7 20) -PREGNADIENE To a solution of 1la-hydroxypregnane-B,ZO-dione in pyridine was added an excess of benzoylchloride. After the solution stood for two hours at room temperature water was added, and the crystals filtered off and washed. The thus obtained 1100-'benzoyloxypregnane3,20-dione was then treated as in Preparation 1 with acetic anhydride to give 3,20-diacetoXy-1100-benz0yloxy-3,17(20)-pregnadiene.

In the same manner as shown above by treating a selected 11a-acyloxypregnane-3,20-dione with an acid anhydride of a different carboxylic acid, 3,20-enol esters of ll00-acyloxypregnane-3,20-dione are obtained wherein the acyloxy groups on the 3- and 20-position are the same and that at the Ila-position is different. Such representative 3.1l,20-triacyloxy-3,17(20)-pregnadienes include: 3,20- dipropionoxy 1100 benzoyloxy 3,17(20) pregnadiene, 3,20 dibutyroxy 1100 benzoyloxy 3,17(20) pregnadiene, 3,20 divaleroxy lla benzoyloxy 3,17(20)- pregnadiene, 3,20 dihexanoyloxy 11a acetoxy-3,17 (20) pregnadiene, 3,20 diacetoxy 1100 propionoxy- 3 1 7 20) -pregnadiene, 3,20-diacetoxy-1100-butyroxy-3,17 (20) pregnadiene, 3,2O-diacetoxy-l100-valeroxy-3,17(20) pregnadiene, 3,20 diacetoxy 110: isovaleroxy 3,17

The last traces of ex- J The drying agent was re- Its structure was confirmed by infra- 4 (20) pregnadiene, 3,20 diacetoxy 1100 heptanoyloxy- 3,17(20) pregna-diene, 3,20 diacetoxy 11a octanoyloxy 3,17(20) pregnadiene, 3,20 diacetoxy tphenylacetoxy-Sl, 17 (20 -pregnadiene, 3,20-diacetoxy-1 10ttoluyloxy 3,17(20) pregnadiene, 3,20 diacetoxy 1'10:- (5 cyclopentylpropionoxy) 3,17(20) pregnadiene, 3,20 diacetoxy 1100 trimethylacetoxy 3,17(20)- pregnadiene, 3,20-diacetoxy-1 1a-chloroacetoxy-3,17 20) pregnadiene, 3,20-diacetoxy-110-bromoacetoxy-3,17(20) pregnadiene, 3,20 diacetoxy 1100 dichloroacetoxy- 3,17(20) pregnadiene, 3,20 diacetoxy 1100 trichloroacetoxy 3,17(20) pregna-diene, 3,20 diacetoxy 11danisyloxy 3,17(20) pregnadiene, 3,20 diacetoxy 110:- gallyloxy 3,17-(20) pregnadiene, 3,20 diacetoxy- 110-mandelyloxy-3,17(20) pregnadiene, 3,20-diacetoxy- 110; toluenesulfonyloxy 3,17(20) pregnadiene, 3,20- diacetoxy 1100 benzenesulfonyloxy 3,17(20) preg- 'nadiene, 3,20 diacetoxy 11a chlorobenzenesulfonyloxy-3, 17 (20 -pregnad-iene, 3,20-diacetoxy-11a-(0z-naphthalenesu'lfonyloxy) 3,17(20) pregnadiene, 3,20 diacetoxy 110: benzenephosphonyloxy 3,17(20) pregnadiene, 3,20 diacetoxy 110: thioglycolyloxy 3,17

(20)-pregnadiene, and the like.

PREPARATION 5.4,17ot-DIBROMO-1la-ACETOXYPREGNANE- 3,20-DIONE One hundred and fifty milligrams (150 milligrams) of 3,1100,20-triacetoxy-3,17(20)apregnadiene was dissolved in eight milliliters of tertiary butyl alcohol and treated with a solution of 128 milligrams of N-bromosuccinimide in fifteen milliliters of tertiary butyl alcohol and with five milliliters of 00.8 Normal sulfuric acid. After two hours of standing the solution was concentrated, diluted with water and the resulting crystals milligrams) collected. Four recrystallizations from alcohol gave white crystals of 11a-acetoxy-4,1700-dibromopregnane-3,20-dione melting at 201 to 203 degrees centigrade with decomposition.

Analysis:

CalculatedforCzsHazOdBrz: C, 51.89; H, 6.06; Br, 30.03 Found: C, 52.16; H, 5.96; Br, 30.01

In a similar manner, using a 3,20-dienol :acylate of the appropriate 1100 acyloxypregnane compound and N-bromosuccinimide, the following compounds are prepared: 4,170: dibromo 1100 propionyloxypregnane- 3,20-dione, '4,1700-dibromo-11a-butyroxypregnane-3,20- dione, 4,17a-dibromo-11a-va1eroxypregnane8,20 dione, 4,1700 dibromo 1100 isovaleroxypregnane 3,20 dione, 4,1700 dibromo 1100 hexanoyloxypregnane 3,20 dione, 4,17a-dibromo-11wheptanoyloxypregnane-3,20-dione, 4,1700-dib1'omo-110t-octanoyloxypregnane-3,20-dione, 4,170: dibromo 1100 benzoyloxpregnane 3,20 dione, 4,1700 dibromo 110: phenylacetoxypregnane 3,20 dione, 4,1700 dibromo 110: toluyloxypregnane 3,20- dione, 4,1700 dibromo 1100 (5 cyclopentylpropionoxy) -.pregnan-e-3,20-dione, 4,1700-dibromo-1 la-tr-imethylacetoxypregnane ii,20-di-one, 4,1700-dibromo-1 10t-chloroacetoxypregnane-3,20dione, 4,1700-dibromo-1la-dichloroacetoxypregnane 3,20 dione, 4,1700 dibromo 11dtrichloroacetoxypregnane-3,20-dione, 4,17a-dib10mO- 11abromoacetoxypregnane-3,20-dione, 4,17-00-dibromo-11aanisyloxypregnane,20-dione, 4,17a-dibromo-11a-gallyloxypregnane 3,20 dione, 4,170: dibromo 11a mandelyloxypregnane 3,20 dione, 4,170: dibromo 110:- thioglycolyloxypregnane-3,20dione, and the like.

PREPARATION 6.4, 17 oc-DICHLORO-l 100-AcEToxY- PREGNANE-3,20-DI0NE Following the procedure given in Preparation 5, but using hypochlorous acid, or a mineral acid with a hypochlorite such as sodium or calcium hypochlorite, or N- chlorosuccinimide or N-chloroacetamide with dilute sulfuric acid, instead of the N-bromosuccinimide, to treat a solution of 3,1la,20-triacetoxy-3,17(20)-pregnadiene in tertiary 'butyl alcohol, 4,17a-dichloro-1la-acetoxypregmane-3,20-dione is obtained.

In the same manner, using a 3,20-dienol acylate of the appropriate pregnane compound and hypochlorous acid or an N-chloroacylamide, the following compounds are prepared: 4,17a-dichloro-1 la-propin0xypregnane-3,20-dione, ,4,l7a-dichloro-11a-butyroxypregnane-3,20-dione, 4, 17u-dicl1loro-l la-valeroxypregnane-3,ZO-dione, 4, l7os-Clichloro-l 1a-isovaleroXypregnane-3,20-dione, 4,17a-dichloro-l1u-heXanoyIoXypregnane-B,20-dione, 4, I7a-diCh101'0- 11a-heptanoyloxypregnane-3,20-dione, 4,17a-dichloro-1 1acctanoyloxypregnane-3 ,20-dione, 4,17a-dichloro-1 lat-benzoxylpregnane-S ,ZO-dione, 4,17a-dichloro-1 la-phenylacetoXypregnane-S,20-dione, 4,17a-dichloro-1 lwtoluyloxypregnane-3,20-dione,' 4,17a-dichloro-1 1a-(/8-cyclopentylpropionoxy)-pregnane-3,20-dione, 4,17a-diChlO1O-11a-t1imethylacetoxypregnane-3,20-dione, 4,17a,-dichloro-11achloroacetoxypregnane-3,20-dione,' 4,17a-diChlO1O-l1a-dichloroacetoxypregnane3,20-dione, 4,17a.-dichloro-1labromoacetoxypregnane-3,20-dione, 4,17a-diChlOIO-l1uanisyloxypregnane 3,20-dione, 4,17a-dichl0l'o-1la-gallyloxypregnane3,20-dione, 4,17a-dichloro-1la-mandelyloxypregnane-3,20-dione, 4,17-dichloro-11a-thioglycolyloxy pregnane-3,20-dione, andthe like.

Example 1 .-1 1 a-acetoxy-J 7a-brom0-4-pregnene- 3,20-dione A solution of 532 milligrams (one millimole) of 4,171:- dibrorno-l1a-acetoXypregnane-3,20-dione in 100 milliliters of dioxane was admixed with 2.5 milliliters of an aqueous solution containing 223 milligrams (two millimoles) of semicarbazide and 164 milligrams (two millimoles) of sodium acetate trihydrate. The color of the reactionmixture changed slowly from very light yellow to orange and gradually back toa pale yellow color. The mixture was stirred overnight at room temperature, and thereafter a solution consisting of 0.52 milliliter of pyruvic acid in five milliliters of water was added. The reaction mixture was then heated to about seventy degrees Centigrade for a period of three hours, thereafter cooled and poured into 200 milliliters of water. The thus-produced 1 1a-acetoxy-17a-bromo-4-pregnene-3,20- dione was extractedfrom the aqueous mixture with three 75-mi1liliter portions of methylene dichloride. The extracts were washed with two fifty-milliliter portions of one percent aqueoussodium hydroxide solution, then with water until the wash-water was neutral, and then dried over anhydrous sodium'sulfate and concentrated to yield 0.452 gram of an oil. This oil containing 11a-acetoxy- 17a-bromo-4-pregnene-3,20-dione was purified by chromatography and recrystallization from acetone and Skellysolve B (hexanes) yielding 162 milligrams of 11a-acetoxy-17a-bromo-4-pregnene-3,20-dione of melting point 166 to 168 degrees centigrade.

Analysis.Calculated for -C23Hs1BrO4: Found: Br, 17.65.

Example 2.11a-benz0yl0xy-1 7a-br0m0-4-pregnene- 3,20-dione A solution of 4,17a-dibromo-1la-benzoyloxypregnane- 3,20-dione dissolved in acetic acid was admixed with a solution of 2,4-dinitrophenylhydrazine hydrochloride and sodium acetate in acetic acid. After stirring for eighteen hours at room temperature, the mixture was poured into water and the 3-(2,4-dinitrophenylhydrazone) of 11abenzoyloxy-l7a-bromo-4-pregnene-3,ZO-dione was obtained by extraction with methylene dichloride. The thus-obtained 2,4-dinitrophenylhydrazone was then heated With para-hydroxybenzaldehyde in acetic acid solution to give 1la-benzoyloxy-17a-bromo-4-pregnene-3,20- dione.

In a similar manner as in the above example but using 3,5-dinitrophenylhydrazone, phenylhydrazine, para-nitrophenylhydrazine, semicarbazide, or aor p-naphthylsemicaroazide (instead of 2,4-dinitrophenylhydrazine) and pyruvic acid, pyruvic aldehyde, or carboxybenzaldehydes' (instead of para-hydroxybenzaldehyde) to treat 11a-beuz-' oyloxy-4,17a-dibromopregnane-3,20-dione, lla-benzoyloxy-17a-bromo-4-pregnene-3,20-dione is obtained.

Example 3 .1 l apr0pi0n0xy-1 7a-chlor0-4-pregnene 3,20-dione In a manner as given in Example 1, 4,17a-dichloro-11apropionoxypregnane-3,20-dione is dehydrohalogenated with semicarbazide and pyruvic acid to yield lla-propionoxy-l7a-chloro-4-pregnene-3,20-dione.

Example 4 .1 1 a- (fl-cyclopentylpropionoxy -17a-br0m0- 4-pregnene-3,20-di0ne In a manner as given in Example 1, 4,17a-dibromo- 1 la-(B-cyclopentylpropionoxy) -pregnane-3,20-dione is dehydrohalogenated with semicarbazide and pyruvic acid to yield 1 lap-cyclopentylpropionoxy) 17 a-bromo-4-pregnene-3,20-dione.

Example 5.11a-butyroxy-J7a-chloro-4-pregnene- 3,20-dione In a manner as given in Example 1, 4,17a-diChl0tO- 11a-butyroxypregnane-3,ZO-dione is dehydrohalogenated with semicarbazide and pyruvic acid to yield lla-butyroxy-l7a-chloro-4-pregnene-3,20-dione.

Example 6.11 a-bulyroxy-l 7a-bromo-4-pregnene- 3,20-dione In a manner as given in Example 1, 4,17a-dibromol1a-butyroXypregnane-3,ZO-dione is dehydrohalogenated with semicarbazide and pyruvic acid to yield lla-butyr oxy-l7a-bromo-4-pregnene-3,20-dione.

Example 7.-] 1 a-mandelyloxy-l 7 a-br0mo-4-pregnene- 3,20-dione In a manner as given in Example 1, 4,17a-dibromo- 11a-mandely1oxypregnane-3,20-dione is dehydrohalogenated with semicarbazide and pyruvic acid to yield 11a.- mandelyloxy-17a-bromo-4-pregnene-3,20-dione.

Example 8.11a-chloroacetoxy-I7a-br0m0-4-pregneri- 3,20-dione In a manner as given in Example 1, 4,17a-dib1'01110- l1a-chloroacetoxypregnane-3,20-dione is dehydrohalogenated with semicarbazide and pyruvic acid to yield 110.- chloroacetoxy-l7a-bromo-4-pregnene-3,20-dione. I

In a manner similar to Example 1 through 8, other lla acyloxy 17oz halo 4 pregnene 3,20 diones are prepared by dehydrohalogenating the corresponding 4,170: dihalo a acyloxypregnane 3,20 dione with organic hydrazine capable of hydrazone formation and a ketaldone advantageously selected from the group consisting of pyruvic acid, pyruvic aldehyde, and benzaldehydes. Representative 1104 acyloxy 17a halo 4- pregnene-3,20-diones thus prepared include: 17u-chloro-' and bromo 110a valeroxy 4 pregnene 3,20- diones, 17tx-chloroand 17OC-b1'0mO-110t-lSOV3-1BI'OXY-4 pregnene-3,20-diones, 17a-chloroand 17a-bromo-11ahexanoyloxy 4 pregnene 3,20 diones, 17a chloro and 17oz bromo 110a heptanoyloxy 4 pregnene- 3,20-diones, 17oc-Cili010- and 17tt-bromo-1la-octanoyloxy- 4 pregnene 3,20 diones, 17a chloroand 17abromo 11a phenylacetoxy 4 pregnene 3,20- diones, 17a chloroand 17a bromo 11a toluyloxy 4 pregnene 3,20 diones, 17a chloroand 170a bromo 11a trimethylacetoxy 4 -pregnene 3,20- diones, 17c: chloroand 17a bromo 11a bromoacetoxy 4 pregnene 3,20 diones, 17a chloroand 170: bromo 11oz dichloroacetoxy 4 pregnene- 3,20 diones, 17a chloroand 170: bromo 11atrichloroacetoxy 4 pregnene 3,20 diones, 17achloroand 170: bromo 111x anisyloxy 4 pregnene 3,20 diones, 17a chloroand 17a bromo- 1106 gallyloxy 4 pregnene 3,20 diones, 17achloroand 17a. bromo 1100 vinylacetoxy 4- pregnene 3,20 diones, 17a chloroand 17abromo 11a acrylyloxy 4 pregnene 3,20 diones, 17a chloroand 17a bromo 11a thioacetoxy 4- pregnene-3,20-diones, and the like.

It is to be understood that the invention is not to be limited to the exact details or exact compounds shown and described, as obvious modifications and equivalents will be apparent to one skilled in the art, and the invention is therefore to be limited only by the scope of the appended claims.

We claim:

1. An 11a acyloxy 170a halo 4 pregnene 3,20- dione of the formula:

wherein Ac is the acyl radical of a hydrocarbon carboxylic acid containing not more than eight carbon atoms and wherein X is selected from the group consisting of chlorine and bromine.

2. 11a acyloxy 17cc chloro 4 pregnene 3,20- dione wherein the acyl radical is of a hydrocarbon carboxylic acid containing up to and including eight carbon atoms.

3. 11a acyloxy 17a bromo 4 pregnene 3,20- dione wherein the acyl radical is of a hydrocarbon carboxylic acid containing up to and including eight carbon atoms.

4. 11a benzoyloxy 17a bromo 4 pregnene- 3,20 dione.

5. 11a acetoxy 17oz bromo 4 pregnene 3,20- dione.

6. 110a propionoxy 17oz chloro 4 pregnene- 3,20-dione.

7. 11a butyroxy 17a bromo 4 pregnene- 3,20-dione.

8. 1111 (6 cyclopentylpropionoxy) 17oz bromo- 4-pregnene-3,20-dione.

9. A process for the selective dehydrohalogenation of a 4,17u dihalo 11a acyloxypregnane 3,20 dione to produce 110: acyloxy 17a halo 4 pregnene- 3,20-dione wherein the halogen atom is selected from the class consisting of chlorine and bromine which comprises: forming a 3-hydrazone of llot-acyloxy-lh-halo- 4-pregnene-3,20-dione, wherein the acyloxy group contains from one to eight carbon atoms, inclusive by reacting 4,17a dihalo 110:. acyloxypregnane 3,20- dione in acid solution with an organic hydrazine and hydrolyzing the 3-hydrazone group by an exchange reaction with a ketaldone to yield the corresponding llez-acyloxy- 1 7a-ha1o-4-pregnene-3,20-dione.

10. A process for the selective dehydrohalogenation of a 4,17a-dihalo-11oc-acyloxypregnane-3,20-dione to produce a acyloxy 17a halo 4 pregnene 3,20- dio-ne wherein the halogen atom is selected from the class consisting of chlorine and bromine which comprises: forming a 3-hydrazone of 1la-acyloxy-17z-ha1o-4-pregnene-3,20-dione, wherein the acyloxy group contains from one to eight carbon atoms, inclusive, by reacting 4,17ot-dihalo-11a-acyloxypregnane-3,20-dione in acid solution with an organic hydrazine and hydrolyzing the 3- hydrazone group by an exchange reaction with a ketaldone selected from the group consisting of pyruvic acid, pyruvic aldehyde, and benzaldehydes to yield the corresponding 1 la-acyloxy-17a-halo-4-pregnene-3,20-dione.

11. A process for the selective dehydrohalogenation of a 4,17u-dihalo-11-a-acyloXyp1'egnane-3,20-dione to produce 110; acyloxy 17a halo 4 pregnene 3,20- dione wherein the halogen atom is selected from the group consisting of chlorine and bromine which comprises: reacting a 4,17-dihalo-11a-acyloxypregnane-3,20- dione, wherein the acyloxy group contains from one to eight carbon atoms, inclusive, with semicarbazide and treating the thus-obtained 3-semicarbazone of 11aacyloxy-17u-ha1o-4-pregnene-3,20-dione with pyruvic acid to obtain the corresponding 11a-acyloxy-17a-halo-4-pregnene-3,20-dione.

12. A process for the selective dehydrohalogenation of 4,17-dichloro-11a-acyloxypregnane-3,20-dione to produce 110a acyloxy a chloro 4 pregnene 3,20- dione, which comprises: reacting 4,17-dichloro-11a-acyloxypregnane-3,20-dione, wherein the acyloxy group contains from one to eight carbon atoms, inclusive, with semicarbazide and treating the thus-obtained 3-semicarbazone of 1la-acyloxy-17a-chloro-4-pregnene-3,20- dione with pyruvic acid to obtain 4,17-diChl0I'O-11ocacyloxy-3,20-dione.

13. A process for the selective dehydrohalogenation of 4,17-dibromo-11a-acyloXypregnane-3,20- dione to produce 11cc acyloxy 17a bromo 4 pregnene 3,20- dione which comprises: reacting 4,17a-dibromo-11aacyloxypregnane-3,20-dione, wherein the acyloxy group contains from one to eight carbon atoms, inclusive, with semicarbazide and treating the thus-obtained 3-semicarbazone of 1lot-acyloxy-17a-bromo-4-pregnene-3,20- dione with pyruvic acid to obtain the corresponding 11aacyloxy-17a-bromo-4-pregnene-3,20-dione.

14. A proces for the selective dehydrohalogenation of' 4,17oz dihalo 11a acyloxypregnane 3,20 dione wherein the acyl group is of a hydrocarbon carboxylic acid containing up to and including eight carbon atoms, which comprises: reacting a 4,17a-diha1o-1lot-acyloxypregnene-3,20-dione, wherein the acyloxy group contains from one to eight carbon atoms, inclusive, with semicarbazide and treating the thus-obtained 3-semicarbazone of 11a-acyloxy-17u-bromo-4-pregnene 3,20 dione with pyruvic acid to obtain the corresponding lla-acyloxy- 17a-halo-4-pregnene-3,20-dione.

No references cited. 

1. AN 11A - ACYLOXY - 17A - HALO - 4 - PREGNENE - 3,20DIONE OF THE FORMULA: 